Anti-Psychotic Composition and Treatment Methods

ABSTRACT

Provided herein are methods of treatment of psychiatric disorders requiring treatment with an antipsychotic drug, such as schizophrenia or schizoaffective disorder, comprising administration of both the antipsychotic drug and a  W. somnifera  plant part, extract, chemical constituent(s) thereof, or a derivative thereof to treat symptoms of the psychiatric disorder. Treatment is typically continued for at least four weeks. A combination dosage form comprising both the antipsychotic drug and the  W. somnifera  plant part, extract, chemical constituent(s) thereof, or a derivative thereof in amounts effective to treat the psychiatric disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/775,565 filed May 11, 2018, which is the United States National Phaseof International Application No. PCT/US2017/050234 filed Sep. 6, 2017,and claims benefit of U.S. Provisional Patent Application No. 62/463,836filed Feb. 27, 2017, each of which is incorporated herein by referencein its entirety.

BACKGROUND OF THE INVENTION

Methods and compositions are provided for treatment of psychoticconditions, such as schizophrenia and schizoaffective disorder.

Current treatment approaches for patients who take medications butexperience breakthrough symptoms in schizophrenia or schizoaffectivedisorder include adjustment of preexisting medications (i.e., dosage) orswitching to another medication or adding other anti-psychoticmedications. Each of these approaches help to curb what are calledpositive symptoms of schizophrenia (e.g., hallucinations, delusions,thought disorganization etc.), but usually do not help much if at allwith negative symptoms (e.g., loss of motivation, loss of energy, slowedthinking and slowed speech production, slowed movements, no interest ingetting things done, etc.) and do not help significantly with generalsymptoms (e.g., depression anxiety, fatigue, etc.).

Recent elaborations of the immune-inflammatory dysregulation theory inschizophrenia have opened new treatment vistas for persons withschizophrenia. An imbalance of pro and anti-inflammatory cytokines andelevated levels of inflammatory markers (e.g., C—reactive protein, S100Band prostaglandin E2) have been reported in subgroups of patients withschizophrenia, especially those experiencing an exacerbation ofsymptoms. These immune-inflammatory alterations are known to impactdopaminergic, glutamatergic and cholinergic neurotransmission, which inturn are linked to the positive, negative and cognitive symptoms notedin schizophrenia. Reviews have concluded that antipsychotic medicationsdo not appear to mitigate immune-inflammatory disturbances. A case hasbeen made for adjunctive treatment of symptoms of schizophrenia usinganti-inflammatory drugs, e.g., Cox inhibitors, since these medicationsshift the immune responsivity from predominantly type-2 to type-1 andinhibit prostaglandin E2 (PGE2) synthesis. A review of 8 randomizedcontrolled trials, including unpublished studies, mostly involvingpatients experiencing symptom exacerbations indicated that adjunctiveCox-2 inhibitors (celecoxib, six studies) or non-selective Cox-1/Cox-2inhibitors (aspirin, two studies) showed a small treatment effect forpositive symptoms of schizophrenia and trend level significance fortotal psychopathology but no effects for negative symptoms. Concernsabout cardiac safety and bleeding risks associated with non-steroidalanti-inflammatory agents (NSAIDS) call for alternative anti-inflammatoryagents to be tested for symptom exacerbations in schizophrenia.

Mismatch Negativity (MMN) is an event-related potential (ERP) capturedin an electroencephalogram (EEG) in humans, but also in other animals,typically in response to a rare deviant sound in a series of standardrepetitive auditory sounds. The detection of the deviant sound generatesthe MMN. The deviant sound can be different in pitch, duration,frequency or intensity from the standard sound. Alteration in mismatchnegativity (MMN) is among the most highly replicated (>200 studies)abnormalities reported in schizophrenia. In long standing schizophrenia,the amplitude of MMN is reduced for a frequency or duration change. In ameta-analysis, Umbricht and Krljes (Mismatch negativity inschizophrenia: A meta-analyses. Schizophrenia Research 2005, 76:1-25)estimated the overall effect size for the MMN abnormality inschizophrenia is 0.99 which is considered large. MMN abnormalities arehighly correlated with impaired day to day and executive functioning aswell as in the acquisition of social skills in people withschizophrenia. Moreover, MMN abnormalities also correlate with negativesymptoms which also impair day to day functioning in persons withschizophrenia.

Standard anti-psychotic drugs used to treat mainly the positive symptoms(examples: hallucinations, delusions, disorganized thinking andbehavior) do not improve MMN. Marketed anti-psychotic drugs mostly aredopamine receptor antagonists and they do not improve the MMNabnormality in schizophrenia which is more closely linked to anotherneurotransmitter system, i.e. N-methyl-D-aspartate glutamate receptors(NMDAR). Moreover, these anti-psychotic drugs do not improve negativesymptoms (examples include: emotional blunting and minimal facialexpressiveness, poverty of speech in response to questions from othersand minimal spontaneous speech, poorly motivated to engage in day to dayactivities, and show low energy and slowed thought processes and comeacross as socially disengaged from others). Therefore, there is asignificant unmet need in improving the neurophysiological abnormalities(e.g. MMN) and negative symptoms in persons with schizophrenia orschizoaffective disorder.

Unlike MMN, elicited passively and automatically by auditory cortex, theP300 event-related potential is elicited during the active detection ofrare target stimuli. It too is severely impaired in schizophrenia evenat first episode. Widespread scalp-recorded amplitude reduction of theauditory P300 event-related potential in schizophrenia is welldocumented and robust. Furthermore, auditory P300 reduction inschizophrenia appears to show trait characteristics, being unimprovedwith resolution of overt psychotic symptomatology; even when variationwith scores on the Brief Psychosis Rating Scale are reported, P300amplitudes remain smaller in schizophrenic than in control subjects.

Another ERP that is reduced in schizophrenia is the gammaband auditorysteady state response (ASSR). When short clicks (1 msec duration) areplayed at 40 Hz, the brain responds by oscillating at the stimulationfrequency (40 Hz) the so-called gammaband. The gammaband ASSR is reducedin long-term schizophrenia, and at first episode, and reductions in thegammaband ASSR, related to NMDA and GABA imbalance, are associated withimpaired cognitive functioning.

There is a need for compositions, active agents and methods of improvingnegative symptoms, mismatch negativity, P300, and gammabandabnormalities in schizophrenia and schizoaffective disorders.

SUMMARY

A method of treating a psychiatric disorder for which an antipsychoticdrug is administered in a patient is provided according to one aspect ofthe invention. The method comprises administering to the patient aWithania somnifera active agent in combination with an antipsychoticactive agent in amounts effective to treat the psychiatric disorder.

According to another aspect, a pharmaceutical dosage form, orcomposition, is provided for use in treatment of a psychiatric disorderfor which an antipsychotic drug is administered. The compositioncomprises comprising an antipsychotic agent and a W. somnifera activeagent in amounts effective to treat the psychiatric disorder, such as apsychotic disorder, such as schizophrenia or schizoaffective disorder,and optionally one or more negative symptoms of the psychiatricdisorder.

According to a further aspect, a W. somnifera active agent is providedfor use in the treatment of a negative symptom of a psychiatricdisorder, e.g. for which an antipsychotic drug is administered.

In the various aspects, the psychiatric disorder may be a psychoticdisorder, such as schizophrenia or a schizoaffective disorder, forexample, selected from the group consisting of: schizophrenia;Schizophrenia, Paranoid Type; Schizophrenia, Disorganized Type;Schizophrenia, Undifferentiated Type; Schizophrenia, Residual Type;Schizoaffective Disorder; Schizophreniform Disorder; DelusionalDisorder; Brief Psychotic Disorder; Other specified SchizophreniaSpectrum and other Psychotic Disorder; Unspecified SchizophreniaSpectrum, and other Psychotic Disorder.

In the various aspects, a negative symptom of the psychiatric disorderis improved in the patient after administration of the W. somniferaactive agent to the patient; stress symptoms, depression, anxiety,and/or excitation symptoms of the psychiatric disorder is improved inthe patient after administration of the W. somnifera active agent to thepatient and/or a sensory or cognitive symptom of the psychiatricdisorder, such as an electroencephalogram response to an auditorystimulus, for example a mismatch negativity abnormality, a P300event-related potential, or a gammaband auditory steady state response,is improved in the patient after administration of the W. somniferaactive agent to the patient.

BRIEF DESCRIPTION OF THE DRAWING(S)

FIGS. 1A-1F provide structures of various W. somnifera active agents.

FIG. 2 is a table showing PANSS (Positive and Negative Syndrome Scale,Kay et al, 1987) and PSS Rating Scale (Perceived Stress Scale, Cohen etal, 2000) Scores.

FIGS. 3A-3D provide graphs showing changes in PANSS Scores in Patientsreceiving W. somnifera Extract or Placebo; Negative Symptoms—Visit 4p=0.025, Visit 5 p=0.001, Visit 6 p<0.001; General Symptoms—Visit 4p=0.007, Visit 5 p<0.001, Visit 6 p<0.001; Total Symptoms—Visit 4p=0.038, Visit 5 p<0.001, Visit 6 p<0.001.

FIG. 4 is a graph showing changes in Perceived Stress Scores in Patientsreceiving W. somnifera Extract or Placebo, Visit 4, p=0.025, Visit 5p=0.051, Visit 6 p=0.004.

FIGS. 5A-5C are graphs showing depression, anxiety, and excitationscores, respectively, in patients receiving W. somnifera Extract orplacebo for patients in Example 1.

FIG. 6 is a graph showing changes in S100b Levels in Patients receivingW. somnifera Extract or Placebo for patients in Example 1.

FIG. 7 is a table providing, from baseline to end of Rx, S100b, hsCRP,and IL-6 levels for patients in Example 1.

FIGS. 8A and 8B are graphs showing correlation between hsCRP and S100Bfor patients receiving W. somnifera Extract or placebo, respectively,for patients in Example 1.

FIG. 9 is a table providing weight, Body Mass Index (BMI) and vitalsigns for patients in Example 1.

FIGS. 10A-10C providing MMN, P300, and gamma-band data, respectively,for patients receiving W. somnifera Extract or placebo for patients inExample 2.

DETAILED DESCRIPTION

The use of numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges are both preceded by the word “about”. In this manner,slight variations above and below the stated ranges can be used toachieve substantially the same results as values within the ranges.Also, unless indicated otherwise, the disclosure of ranges is intendedas a continuous range including every value between the minimum andmaximum values. As used herein “a” and “an” refer to one or more.

A “patient” is a human being and does not imply a doctor-patientrelationship. “Treatment” of a patient refers to improvement of one ormore clinically-relevant symptoms of a stated disorder, disease, orcondition. In the context of schizophrenia, schizoaffective disorder,and other disorders listed above, there are symptoms that are positive,negative, or general. Positive symptoms include: hallucinations,delusions, bizarre thoughts, disorganized thoughts, etc. Often, positivesymptoms respond to available anti-psychotic drugs. Negative symptomsinclude: diminished facial emotionality (facial expressions are woodenand fixed and often without a smile even when it is appropriate), lackof interest and detachment from family, relatives, friends, or fellowpatients etc., uncommunicative or minimally communicative and withdrawn,neglect of personal grooming and hygiene, distant and apathetic towardsfamily, friends, clinical staff during conversations, little to noenergy, no motivation, difficulty with abstract thinking, can be veryconcrete in response to the meanings of proverbs or common day to daycategorizations, barely speaks or even if he or she does, minimal outputand no normal elaboration of sentences, rigid thinking and repetition ofideas, slowed down thinking etc. In contrast to positive symptoms,negative symptoms do not respond to available antipsychotic drugs.General symptoms include: somatic preoccupation with several bodilysymptoms, anxiety, depression, guilt feelings, tension, overall slowingdown of speech and activity inadequately co-operative, poor attentionand concentration, not fully oriented, exhibiting poor judgement andinsight, poor impulse control, social avoidance, etc. In variousaspects, the PANSS scale, and subscales thereof, or the Perceived StressScale, can be utilized to judge improvement of symptoms as describedherein. In another aspect, the symptom is cognitive sensory response,such as an electrofrequency hologram event-related potential, such as amismatched negativity, an auditory P300 event-related potential, and/ora reduced gammaband auditory steady state response. These cognitive orsensory symptoms do not respond to available anti-psychotic drugs.Although often effective at treating positive aspects of schizophrenia,schizoaffective disorder and similar disorders addressed above,antipsychotic drugs are largely ineffective at treating negativesymptoms and in many aspects general symptoms, and attempts at use ofantidepressants, such as selective serotonin reuptake inhibitors (SSRIs)and the like have not held promise. By “improved,” “improving,” or“improvement” in relation to a symptom of a disorder, disease, orcondition, it is meant that a measurable metric or measurement of thesymptom is moved towards a normal value for a patient and away from avalue that is characteristic of the disease or condition. For example,improvement of the negative symptom of the patient being uncommunicativeor minimally communicative and withdrawn would mean the patient is morecommunicative and engaging.

Provided herein are methods of treating various psychiatric disordersusing a composition comprising a W. somnifera composition, e.g., anactive agent, such as a composition prepared from the medicinal herb W.somnifera, often referred to as ashwagandha, and typically is in theform of an extract of W. somnifera. The W. somnifera agent, for example,the extract of, e.g., the roots and/or leaves of, a W. somnifera plant,are administered to improve symptoms of the psychiatric disorder asdescribed above, and in one aspect to improve one or more negativesymptoms of the psychiatric disorder, and optionally one or more generaland/or one or more positive symptoms of the psychiatric disorder.

In one aspect, a method of treating a patient with a psychiatricdisorder is provided. The psychiatric disorder includes psychoticdisorders (or psychoses), and includes any disorder for which anantipsychotic drug is administered. Non-limiting examples of suchdisorders include: a schizophrenia disorder (295.xx according toDSM-IV-TRTM and DSM-STM, and F20.9 according to InternationalClassification of Disease, or ICD-10-CM codes); 295.30 Schizophrenia,Paranoid Type; 295.10 Schizophrenia, Disorganized Type; 295.90Schizophrenia, Undifferentiated Type; 295.60 Schizophrenia, ResidualType; 295.70 (F25.0, F25.1) Schizoaffective Disorder; 295.40 (F20.81)Schizophreniform Disorder; 297.1 (F22) Delusional Disorder; 298.8 (F23)Brief Psychotic Disorder; 298.8 (F28) Other specified SchizophreniaSpectrum and other Psychotic Disorder; 298.9 (F29) UnspecifiedSchizophrenia Spectrum and other Psychotic Disorder. DM and ICD codesare provided for exemplary purposes only. In one aspect, the treatedpatient has an exacerbation of one or more symptoms, e.g., one or morenegative, general, or cognitive/sensory symptoms of a psychiatricdisorder of which an anti-psychotic drug is administered, such asschizophrenia or a schizophrenic disorder. The method comprisesadministering to the patient an amount of an antipsychotic drug and anamount of a composition comprising leaves and/or roots of a W. somniferaplant or an extract of, e.g., the roots and/or leaves of, a W. somniferaplant, or portions thereof, effective to treat the patient, e.g., toimprove a negative symptom and/or a cognitive/sensory symptom of apsychiatric disorder of which an anti-psychotic drug is administered,such as schizophrenia or a schizophrenic disorder. In one aspect, theextract is prepared by alcohol-extraction of the roots and/or leaves ofa W. somnifera plant. In another aspect, the extract is prepared bywater-extraction of the roots and/or leaves of a Withania somniferaplant.

Withania somnifera Dunn. is also referred to as Ashwagandha in Ayurvedicmedicine, or as to Indian Ginseng. It is reputed for promoting healthand longevity by increasing defense against disease, arresting the agingprocess, revitalizing the body in debilitating conditions, and is oftenreferred to as an adaptogen. Commercial preparations typically includeground roots and leaves, or extracts of roots and leaves. The roots andleaves of the W. somnifera plant, and extracts thereof, have the desiredchemical constituents providing the extract its utility in the methodsdescribed herein. Nevertheless, although reference is made to the rootsand leaves of the W. somnifera plant, other plant parts may find use inpreparation of standardized extracts, so long as activity of thecomposition according to the methods described herein is retained, andtoxicity is minimized.

Extracts of W. somnifera (WSE) have demonstrated immunomodulatory andanti-inflammatory actions in animal studies, enhancing type-1 immuneresponse and cytokine production while modulating production of acutephase reactants, Cox 2 inhibition, and inhibition of NF-kB inflammatorysignaling pathways. WSE has also shown anxiolytic, pro-cognitive, andanti-arthritic benefits and appears to have fairly good safety in earlyhuman studies. A WSE extract inhibited NF-kB (an inflammatory signalingpathway) in mononuclear cells from healthy controls and patients withrheumatoid arthritis, and also suppresses the production of severalpro-inflammatory cytokines. WSE attenuates pro-oxidant and inflammatoryactivity in astrocytes and microglia. Based on animal and humanimmune-inflammatory data, it was posited that standardized extracts ofW. somnifera would prove beneficial for recently exacerbated symptoms inpatients with schizophrenia.

Various unique compounds are found within the extract of, e.g., theroots and/or leaves of, a W. somnifera plant, and can be obtained byeither extraction or purification methods using parts of, e.g., theroots and/or leaves of, a W. somnifera plant, or by syntheticmanufacture. Thus, leaves and/or roots of a W. somnifera plant or anextract of, e.g., the roots and/or leaves of, a W. somnifera plantcomprise one or more “W. somnifera active agent”, which comprisespharmacologically active compositions (active agents) found in theextract of, e.g., the roots and/or leaves of a W. somnifera plant, suchas withanolide glycosides, sitoindosides, sapogenins, andoligosaccharides found therein, and aglycone derivatives thereof, suchas withaferin A (aglycone), and derivatives thereof (see, e.g., U.S.Patent Application Publication Nos. 20040166184, 20130115316, and20150320771, incorporated herein by reference). The W. somnifera activeagents are useful in the methods of treating the psychological disordersdescribed herein, such as schizophrenia, schizoaffective disorder, orother disorders for which antipsychotic drugs are prescribed. Chemicalconstituents, e.g., active agents, found in W. somnifera, and extractsthereof, such as aqueous or alcohol extracts, include the following:Withaferin A (FIG. 1A), Withanolide D (FIG. 1B), Sitoindoside VII (FIG.1C), Sitoindoside VIII (FIG. 1D), Sitoindoside IX (FIG. 1E), andSitoindoside X (FIG. 1F).

The following depicts a Withaferin A derivative (See, U.S. PatentApplication Publication No. 20150320771):

where R¹ is H, C₁-C₃ alkyl, or C₁-C₄ alkoxyl, R² is H or C₁-C₃ alkyl, R³is H or HO, and

is a single or double bond. Methods of preparing the withaferin Aderivative described above are described in U.S. Patent ApplicationPublication Nos. 20130115316 and 20150320771.

Typically, commercially available extracts of W. somnifera lack thebeneficial chemical constituents in appreciable quantities for whichashwagandha is reputed for, instead they contain: traces ofglycowithanolide or are completely devoid of glycowithanolides; largeamounts of withanolide aglycones; high levels of polysaccharides, andlow levels of oligosaccharides; and toxic tropane-type alkaloids orscopolamine. The quality of W. somnifera extract is improved by usingthe process reported in the U.S. Pat. Nos. 6,153,198 and 6,713,092, andis a suitable process for obtaining the extract of W. somnifera.Additional uses for the extract of W. somnifera, and compositionscontaining the extract are described in U.S. Pat. Nos. 7,318,938, and7,250,181. The extraction procedure provides an extract powdercomposition, which contains all the desired bioactive ingredients inoptimized concentrations and ratios. The composition is stable,bio-available, and non-toxic.

In one aspect, an extract is prepared from W. somnifera plant parts. Forexample, on one aspect, dried roots and/or leaves from plants are waterextracted, typically at a temperature of less than 60° C., at a suitabletemperature, filtered and concentrated as needed, yielding a productcomprising (e.g., by HPLC) at least 8% (as used herein w/w unlessindicated otherwise) withanolide glycosides, at least 32%oligosaccharides, and at most 2% free withanolide aglycones (e.g., aswithaferin A). When dried and powdered, a free-flowing brown to darkbrown powder is formed that is approximately 97% soluble in water. Inone aspect, capsules or tablets are prepared according to standardformulation methods known to those of ordinary skill in thepharmaceutical and formulary arts, including such excipients asmicrocrystalline cellulose, carboxymethylcellulose, and variouspreservatives, lubricants or flowing agents, anticaking agents, anddissolution enhancers, such as fumed silica. An exemplary product havingthese specifications is SENSORIL®, available from Natreon, Inc. of NewBrunswick, N.J. In one example, a W. somnifera plant extract wasprepared essentially as described above by aqueous extraction and storedunder normal storage conditions and accelerated storage conditions,yielding withanolide glycoside ranges from 15.96% to 16.85%, WithaferinA ranges from 1.21% to 1.89%, and oligosaccharide ranges from 40.30% to42.11%, indicating the stability of the composition.

Additional W. somnifera extracts, includingindolealkylamino-withasteroid conjugates, useful for the methods andcompositions described herein are described

Using that procedure, any part of the plant of W. somnifera can be usedto obtain the extract provided it is devoid or has a trace amount oftoxic tropane-type alkaloid, scopolamine. Preferred extract is thestandardized extract containing glycowithanolides, withanolide agylconeand oligosaccharides and devoid or have a only a trace amount of toxictropane-type alkaloid.

The extraction procedure of U.S. Pat. No. 6,153,198 provides: a highpurity W. somnifera plant extract composition with substantially lowlevels of cytotoxic withaferin A (aglycone), in the form of a stable,free-flowing light yellow-to-brown herbaceous powder composition. Atypical dosage range for providing enhanced cognition and augmentedlearning facility in the geriatric population of the extract is fromabout 200 to 800 mg/day. The described biologically-enhancingcomposition described therein includes in one aspect, by weight, (a) atleast 3% of withanolide glycosides and sitoindosides, (b) at least 3% ofoligosaccharides, e.g., with a mol. wt. of <2000, and (c) less than 0.5%of free withaferin A (aglycone), wherein the ratio of (a):(c) is75-95:25-5 and the ratio of (a):(b) is 40-60:60-40. Preferably, thecomposition is at least 90% soluble, the ash content of this compositionis less than 8%, and its moisture content is less than 5% (w/w).

The exemplary standardized extract reported in U.S. Pat. No. 6,713,092is contained in Table 1.

TABLE 1 exemplary content of a standardized W. somnifera extractANALYSIS SPECIFICATION RESULTS Identity (HR) HPLC - FDA spectrumConfirms i) Total withanolide glycoside    ≥8% 12.7% conjugates (ByHPLC) ii) Oligosaccharides (By    ≥25% 36.3% HPTLC) iii) Free withaferinA and   ≤2.0% 1.60% Equivalents - withanolide aglycones (By HPLC) HeavyMetals (as PB)  ≤0.002% Complies Arsenic (As)  ≤0.0002% CompliesSulfated Ash    ≤8% Complies Moisture content    ≤5% 3.50%Microbiological Test Total Aerobic plate count <10³/g 2 × 10² CFU/gmEscherichia coli Absent in 1 g Ni Salmonella Absent in 10 g Nil Ratio ofwithanolide glycoside 75-95 to 25-5 89:11 conjugates and free withaferinA (aglycones) Ratio of withanolide glycoside 12-35 to 82-65 26:74conjugates and oligosaccharides PRODUCT DESCRIPTION Appearance FinePowder Color Brown to brownish green Odor Characteristic Taste Mildbitter Water-soluble ≥80% extractive value

In aspects, the W. somnifera extract composition comprises 8% or greaterwithanolide glycosides and sitoindosides, 32% or more ofoligosaccharides, e.g., from 45%, to 60%, or from 45% to 55% ofoligosaccharides and 2% or less of withaferin A, e.g., from 0.15% to0.30%, e.g., from 0.19% to 0.30% withaferin A (all by HPLC).

Antipsychotic drugs, as used herein are a class of drugs often used totreat positive symptoms of schizophrenia, schizoaffective disorder andsimilar disorders addressed above. Table 2 provides examples ofcommonly-prescribed antipsychotic agents, and typical, exemplary, andnon-limiting prescribed oral dosage ranges. Table 3 provides examples ofcommonly-prescribed antipsychotic agents, and typical, exemplary, andnon-limiting prescribed intramuscular (IM) dosage ranges.

TABLE 2 oral antipsychotic medications Examples of BrandCommonly-Prescribed Generic name names Oral Dose ranges AtypicalAntipsychotics asenapine SAPHRIS ® 5 mg-20 mg daily quetiapineSEROQUEL ® 150 mg-800 mg daily lurasidone LATUDA ® 20 mg-160 mg dailyolanzapine ZYPREXA ® 5 mg-25 mg daily iloperidone FANAPT ® 12 mg-24 mgdaily paliperidone INVEGA ® 3 mg-12 mg daily aripiprazole ABILIFY ® 2mg-30 mg daily brexpiprazole REXULTI ® 2 mg-4 mg daily risperidoneRISPERDAL ® 1 mg-8 mg daily cariprazine VRAYLAR ® 1.5-6 mg dailyziprasidone GEODON ® 40 mg-160 mg daily Clozapine CLOZARIL ® 100 mg-900mg daily Miscellaneous antipsychotics Pimozide ORAP ® 1 mg-10 mg dailyMolindone MOBAN ® 20 mg-225 mg daily Loxitane LOXAPINE 60 mg-250 mgdaily Haloperidol HALDOL ® 1 mg-30 mg daily Phenothiazine antipsychoticsChlorpromazine THORAZINE ® 200 mg-800 mg daily Trifluoperazine STELAZINE15 mg-40 mg daily Perphenazine TRILAFON 12 mg-32 mg daily FluphenazinePROLIXIN ® 5 mg-40 mg thioridazine MELLARIL ® 200 mg-800 mg dailyThioxanthenes Thiothixene NAVANE ® 20 mg-60 mg daily

TABLE 3 injected (IM), long-acting antipsychotic medications Genericname Commonly-Prescribed Dosages Fluphenazine Decanoate 6.25 to 50 mg IMQ 2 weeks Haloperidol Decanoate 75 to 200 mg IM Q 4 weeks Risperidone(RISPERDAL 12.5 to 50 mg IM Q 2 weeks CONSTA ®) Paliperidone palmitate(INVEGA 39 to 234 mg IM Q 4 weeks SUSTENNA ®) Paliperidone palmitate(INVEGA ® 273 to 819 mg IM Q 12 weeks TRINZA) Aripiprazole (ABILIFY 300to 400 mg IM Q 4 weeks MAINTENA ®) Aripiprazole (ARISTADA ®) 441 to 882mg IM Q 4 weeks (or 882 mg IM Q 6 weeks, or 1064 mg IM Q 2 months)Olanzapine (ZYPREXA ® RELPREV) 150 to 405 mg IM Q 2 or 4 weeks *IM =intramuscular

As above, the amount of W. somnifera active agent, e.g., extract,administered to a patient is an amount effective to achieve relief orimprovement of one or more symptoms of schizophrenia, schizoaffectivedisorder, or any other condition for which an antipsychotic drug isadministered to a patient. The W. somnifera plant material or extractthereof can be administered concurrently with the antipsychotic drug,though not necessarily.

In one aspect, a dosage form composition is provided including anantipsychotic drug and a W. somnifera active agent, e.g., an extract ofW. somnifera plant material, such as an extract of roots and/or leaves,in amounts effective to treat schizophrenia, schizoaffective disorder,or a condition for which an antipsychotic drug is prescribed.

The active agents, e.g., in the form of compounds or extracts, may becompounded or otherwise manufactured into a suitable composition foruse, such as a pharmaceutical dosage form or drug product in which thecompound is an active ingredient. Compositions may comprise apharmaceutically acceptable carrier, or excipient. An excipient is aninactive substance used as a carrier for the active ingredients of amedication. Although “inactive,” excipients may facilitate and aid inincreasing the delivery or bioavailability of an active ingredient in adrug product. Non-limiting examples of useful excipients include:antiadherents, binders, rheology modifiers, coatings, disintegrants,emulsifiers, oils, buffers, salts, acids, bases, fillers, diluents,solvents, flavors, colorants, glidants, lubricants, preservatives,antioxidants, sorbents, vitamins, sweeteners, etc., as are available inthe pharmaceutical/compounding arts.

Useful dosage forms include: intravenous, intramuscular, orintraperitoneal solutions, oral tablets or liquids, topical ointments orcreams and transdermal devices (e.g., patches). In one aspect, thedosage form is an oral capsule, liquid, or table prepared according tostandard methods and with standard excipients, as are broadly-known inthe pharmaceutical arts. The capsule, tablet, liquid, or other oraldosage form may be designed to release the active ingredients containedtherewithin as a bolus or over time, and the active ingredients can bedistributed within the dosage form, and within the materials used tomake up the dosage form for extended delivery, or for delivery atdifferent time frames post-ingestion. Extended-release oral dosage formsare prepared according to well-known techniques in the pharmaceuticalarts. In another, the composition is an intramuscular or intravenousdosage form, and includes a sterile solution comprising the activeingredients, and a solvent, such as water, saline, lactated Ringer'ssolution, or phosphate-buffered saline (PBS). Additional excipients,such as polyethylene glycol, emulsifiers, salts, rheology modifiers, andbuffers may be included in the solution. In another aspect, the dosageform is a spray or aerosol for inhaled or nasal administration, as areknown in the pharmaceutical arts.

Example 1

A randomized, double-blind, placebo controlled study was performed basedon a total of 66 patients with Schizophrenia or Schizoaffective Disorderwho were experiencing an exacerbation of symptoms, and the efficacy datais based on n=33 subjects who received the Standardized extract of W.somnifera—SENSORIL® n=33, and n=33 who received placebo, the treatmentwas provided for 12 weeks. The dosage of SENSORIL®—Standardized Extractof W. somnifera was titrated from 500 mg/day for the first week to 1000mg/day for the balance of the study.

The dosage of the Standardized Extract of W. somnifera—SENSORIL® wasadjusted as follows: 250 mg by mouth twice daily (i.e., total dailydosage of 500 mg/day) for one week, and then increased to 500 mg bymouth twice daily (i.e., total daily dosage of 1000 mg/day) for thebalance of the study, i.e., 11 weeks. The capsules were taken with wateror juice and patients were advised to take it with food and not on anempty stomach.

Positive, negative, and general symptoms are added up to come up with atotal symptom score. One of the common scales to measure change inclinical trials in schizophrenia and/or schizoaffective disorder is thePositive and Negative Syndrome Scale—PANSS, and this scale was used tomeasure symptoms and improvements in the study on which the treatmentclaims are based. Subscales within the PANSS scale capture the Positive,Negative, General and Total symptoms. The symptoms of perceived stresswere measured using the Perceived Stress scale which is also widely usedin several studies.

When added to antipsychotic drugs (taken for at least 4 weeks or more)in men or women aged 18 years or older with a diagnosis of Schizophreniaor Schizoaffective Disorder who have experienced an exacerbation ofsymptoms, a Standardized Extract of W. somnifera—SENSORIL® providedsignificant benefits for Negative, General and Total symptoms comparedto those receiving a placebo.

In these same patients, the same Standardized Extract of W.somnifera—SENSORIL® also significantly improves scores on a known stressscale compared to those receiving a placebo.

The time to onset of improvements in Negative, General and Totalsymptoms for the above patients were first noticed at 4 weeksafter—SENSORIL® was started, and continued throughout the 12 weeks oftreatment with—SENSORIL®.

The time to onset of improvement in stress scores in the same patientswith—SENSORIL® also followed the same time course as the Negative,General and Total symptoms.

During the 12 week study, in the group that received the StandardizedExtract of W. somnifera—SENSORIL®, there were significantly fewer dosageadjustments of anti-psychotic drug doses (or the addition of a secondantipsychotic drug) compared to those who received placebo.

In further detail, sixty-six randomized patients (n=33 per group)provided efficacy data. Beginning at 4 weeks, and continuing to the endof treatment, WSE produced significantly greater reductions in PANSSnegative, general and total symptoms (Cohen's d: 0.83, 0.76, 0.83), butnot positive symptoms, when compared to placebo. PSS scores improvedsignificantly with WSE treatment compared to placebo (Cohen's d: 0.58).CRP and S100B declined more in the WSE group but were not significantlydifferent from placebo. Adverse events were mild to moderate andtransient; somnolence, epigastric discomfort, and loose stools were morecommon with WSE. In conclusion, this study suggests that adjunctivetreatment with a standardized extract of Withania somnifera providessignificant benefits for negative, general, total, and stress symptomsin recently exacerbated patients with schizophrenia.

Methods

Patients included male or female outpatients aged 18 to 75 years of anyrace, with DSM IV-TR Schizophrenia or Schizoaffective Disorder affirmedby the Mini International Neuropsychiatric Interview (MINI, Sheehan, D.V., et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.):the development and validation of a structured diagnostic psychiatricinterview for DSM-IV and ICD-10, J Clin Psychiatry. 1998; 59 Suppl20:22-33) and supplemented by history from medical records and referringclinicians, were recruited. All subjects provided written informedconsent. At study entry, the Positive and Negative Syndrome Scale(PANSS) total score had to be ≥60, with a score of 5 on any one of theitems of the positive symptom cluster (delusions, conceptualdisorganization, hallucinatory behavior, excitement, grandiosity,suspiciousness/persecution, hostility), or unusual thought content.Alternatively, a score of at least 4 on any two items of this symptomcluster qualified patients for study inclusion. Moreover, symptomexacerbation had to extend greater than two weeks, but less than oneyear and patients had to be receiving antipsychotic agents for at least4 weeks. Women in the reproductive age group were required to have anegative pregnancy test at entry. Additional exclusion criteria includedpositive tests for illicit drugs (marijuana and alcohol use were allowedon a case by case basis), unstable medical disorders, pregnancy orbreastfeeding, known allergy to WSE, or conditions requiring immediatepsychiatric or medical hospitalization. Subjects receiving antibiotics,antiviral or anti-parasitic medications; those receivingimmunosuppressive therapy; and subjects taking daily NSAIDs or doses ofaspirin greater than 81 mg/day were excluded.

The study was a 12-week, double-blind, randomized, placebo-controlledtrial of a standardized extract of WSE (SENSORIL®, target dosage: 1000mg/day) added to ongoing antipsychotic treatment in moderatelysymptomatic patients with either schizophrenia or schizoaffectivedisorder.

Subjects meeting all eligibility criteria progressed to a 1:1randomization to WSE or placebo. A computerized randomization schedulewas generated, and IDS (Investigational Drug Service) secured the studymedications and blinded codes. All assessments were conducteddouble-blind (rater and patient blinded). The WSE and placebo wereconstituted as identical gelatin capsules. The WSE capsules contained250 mg of the standardized extract along with inactive ingredients,including cellulose, croscarmellose, silicon dioxide, magnesium citrate,and others. The placebo capsules had the same inactive ingredients andfill weight as the WSE capsule but did not contain the WSE extract. Tomask the smell of the WSE capsules, the placebo capsules were exposed tofully closed cloth pouches that contained WSE powder. After a couple ofdays, the odor permeated the placebo capsules, making them smell likethe WSE capsules. Study medication or placebo was initiated on day 1 byoral route and was given BID. At this stage, the active group received250 mg of WSE twice a day for a total daily dose of 500 mg/day. This wastitrated to 500 mg BID, for a total daily dose of 1000 mg/day, at week2. This dosage was maintained for the rest of the study, unlesstolerability dictated a lower dosage. Pill counts and reconciliation ateach visit served as a measure of adherence. Including the screeningvisit, there were a total of 6 visits. The treatment period with studymedication was 12 weeks.

The primary outcomes were assessed using the Positive and NegativeSyndrome Scale (Kay S. R. et al., Fiszbein A, Opler L A: The positiveand negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull.1987; 13:261-276). Secondary outcomes included the Perceived StressScale (PSS, Cohen et al, 2000), which evaluated stress levels ofsubjects during the study, and the Clinical Global Impressions Scale, todetermine any improvement. These assessments were conducted at everyvisit during the study. Immune-inflammatory laboratory measures includedthe cytokines IL-2, IL-4, IFN-γ, and IL-6, as well as hsCRP and S100B;these were measured in serum at screening and at the end of treatment.The cytokines were assayed using a multiplex Luminex® bead technologyassay (Invitrogen, Camarillo, Calif.). The lower limit of detectionsensitivity of the assay for human IL-2 was <6 pg/mL, IL-4 was <5 pg/mL,IL-6 was <3 pg/mL, and IFN-γ was <5 pg/mL. High sensitivity C-reactiveprotein (hs-CRP) was measured in mg/L units using a nephelometric methodthat employed latex particles coated with CRP monoclonal antibodies. Thelower limit of detection sensitivity of this commercially availableassay (Quest Diagnostic Labs) is 0.2 mg/L. S100B was measured in serumin picograms/ml using a commercially available sandwich ELISA (EMDMillipore, MA, USA). The lower limit of detection sensitivity of theS100B assay was 2.7 picograms/ml with the intra- and inter-assay CVsbeing <4.8% and 4.4% respectively.

The primary efficacy measure was change from baseline to end of thetreatment in PANSS total and PANSS positive, negative and generalsymptoms scores. Secondary efficacy measures included proportions ofpatients in each treatment group meeting at least 20% improvement inPANSS total, positive, negative, and general symptom scores. Baseline toend of treatment PSS total scores and proportions in each treatmentgroup achieving at least 20% improvement in PSS scores were alsosecondary efficacy outcomes. Furthermore, time to onset of anyimprovements in PANSS or PSS scores (i.e. change from baseline to eachvisit) between treatments was assessed as a secondary outcome as wereproportions of patients showing improvement on the CGI-improvementsubscale at the end of treatment.

Additional secondary outcomes assessed psychotropic medication changes,i.e. increase in antipsychotic drug dosage, switch of antipsychoticdrug, or the addition of a second antipsychotic medication betweentreatments. Similar changes in mood stabilizers, anxiolytic/hypnotics,or antidepressants were also evaluated. Changes in levels of hsCRP,S100B, and cytokines from baseline to end of treatment determined if WSEsignificantly diminished inflammatory-immune indices compared toplacebo, and whether any reductions mediated improvement in clinicaloutcomes.

In the absence of prior data for WSE in treating symptoms ofschizophrenia, we adopted a recommendation that a sample size of 40 to100 subjects in adjunctive treatment trials in schizophrenia couldprovide reasonable guidance for initial studies. Moreover, initialpositive studies with celecoxib or aspirin had sample sizes ranging from50 to 70 subjects. An intent-to-treat analysis was planned of allsubjects who were randomly assigned to either WSE or placebo, and whohad at least one pre- and post-randomization primary efficacy outcomemeasure (PANSS total and subscale scores). For the primary efficacyanalyses, a student's t-test was used to examine differences betweentreatment groups in changes from baseline to end of treatment in PANSS(total and subscale scores) and PSS scores in the intent-to-treatsample. A mixed-model repeated measures analysis using anauto-regressive covariance matrix examined the robustness of the primaryanalyses and the time to improvement in PANSS and PSS scores frombaseline to end of treatment. This model used treatment, visit andtreatment*visit interaction as fixed effects and subjects as randomeffects.

Secondary outcomes included proportions of subjects in each treatmentgroup who achieved ≥20% improvements and were compared using achi-square test. Cohen's d (effect size) was determined using the groupmean change between treatment and placebo from baseline to studyendpoint, divided by the pooled standard deviation. The number needed totreat (NNT) for ≥20% response rates was calculated as 100/absolute riskreduction. Proportions of subjects in each treatment group whoexperienced anti-psychotic or other psychotropic medication changes werecompared using Fisher's exact test. Two—tailed hypotheses testing wasconducted, and a p value of ≤0.05 was considered statisticallysignificant. Statistical analyses was undertaken blind to treatmentassignment.

As distributions of cytokine, hs-CRP or S10013 levels are often skewedor affected by the lower limits of the detection sensitivity of theassays, it was planned to transform the data to normalize thedistribution and/or use non-parametric statistics such as theMann-Whitney U or Wilcoxon Signed Rank Tests to test statisticalsignificance between or within treatment groups respectively.Immune/inflammatory changes were compared with changes in PANSS(subscales and total) and PSS scores using Pearson's or Spearman'scorrelations. Safety analyses of vital signs, EKG, laboratory measures,and body weight were evaluated either as continuous or categoricalvariables (for instance—normal, abnormal etc.). Reportedtreatment-emergent adverse events were grouped by organ-system andtabulated by treatment assignment, and rates between treatments werecompared using chi-square or Fishers Exact test for categoricalvariables and t-tests for continuous variables.

Results

82 subjects were screened for consent and eligibility, and 68 subjectswere randomly assigned to WSE (n=34) or placebo (n=34). One subject ineach treatment group did not take the allocated treatment and providedno further data. Therefore, sixty-six patients (n=33 subjects in eachtreatment arm) formed the efficacy defined intent to treat population.Fifty-nine subjects (89.4%) completed the study, 28 (84.9%) in the WSEgroup and 31 (93.9%) in the placebo arm, with no statisticallysignificant differences between treatments.

None of the demographic, illness or medication characteristics (Table 4)differed significantly between the treatment groups. Patients compriseda cohort in their mid to late 40s, mainly with a DSM-IV-TR diagnosis ofSchizophrenia (61%), and with at least 20 years of illness and more thanseven life-time hospitalizations. The mean duration of the currentsymptom exacerbation was nearly 16 weeks. On average, patients wereobese (Body Mass Index just over 30 mg/kg2), and 62% were currentcigarette smokers. The majority of patients in either treatment group(87.9% in WSE, and 90.9% Placebo) received atypical antipsychotic agentsin similar daily olanzapine equivalents (Leucht S. et al., DoseEquivalents for Antipsychotic Drugs: The DDD Method. Schizophr Bull2016; 42:S90-S94), and four subjects each in the WSE and in the placebogroup received more than one antipsychotic agent. Five WSE and threeplacebo assigned subjects received clozapine. Other psychotropic agents,including anti-depressants, mood-stabilizers, anxiolytics,hypnotic-sedatives and anti-cholinergic agents were fairly evenlydistributed between treatment groups. Adherence ranged from 82% to 100%among the majority of patients (63/66), with no significant differencesbetween the two treatment groups.

TABLE 4 Demographic, Illness and Medication Characteristics t-test orSENSORIL ® Placebo χ², (n = 34) (n = 34) df, p Age, mean (SD), y 45.18(12.90) 47.38 (11.37) 0.75, 66, ns* Gender, male/female, n 21/13 14/20ns Race, White/African American, n 12/22 20/14 ns Diagnosis, 21/13 18/16ns Schizophrenia/Schizoaffective, n Age at onset of 1^(st) episode, mean24.32 (10.89) 24.00 (7.67) 0.14, (SD), y 66, ns Number of lifetimepsychiatric 7.71 (6.45) 7.76 (6.90) 0.04, hospitalizations, mean (SD)66, ns Duration of illness, mean (SD), y 20.85 (12.26) 23.38 (11.61)0.83, 66, ns Duration of current symptoms, 16.91 (11.02) 14.84 (11.12)0.75, mean (SD), weeks ** 62, ns Smokers (current smokers) n 22 (67) 19(58) ns (%) ** Body Mass Index, BMI, mean 30 (7.56) 30.33 (8.04) 0.17,(SD) kg/m² 64, ns Psychotropic Medications ** Atypical Antipsychotics, n28 31 ns 0.33, OLZ* Equivalent (SD), mg/day 16.39 (8.21) 17.37 (13.64)57, ns Typical Antipsychotics, n  7  8 ns Antidepressants, n 14 17 nsMood Stabilizers, n  9 13 ns Anti-anxiety, n 10 11 ns Hypnotic/Sedative,n  7  5 ns Anti-Cholinergic, n  8 11 ns *ns = statistically notsignificant, ** n = 33 in each group, χ² or Fisher's Exact Test, OLZ =Olanzapine

As noted in FIG. 2 the WSE treated group achieved significantly betteroutcomes on the PANSS negative, general and total symptom scorescompared to those assigned to placebo. Treatment effect sizes favoringWSE ranged from large (negative and total symptoms, Cohen's d=0.83) tomedium (general symptoms, Cohen's d=0.76, Cohen J. Quantitative Methodsin Psychology, A Power Primer. Psychological Bulletin, 1992, Vol. 112.No. 1, 155-159) (Table 5). PANSS positive symptom scores improved morein the WSE group compared to placebo but did not achieve statisticalsignificance (Cohen's d=0.48).

TABLE 5 Effect sizes and number needed to treat (NNT) for PANSS and PSSin favor of Sensoril Cohen's d Size of Effect PANSS Positive 0.48 SmallPANSS Negative 0.83 Large PANSS General 0.76 Medium PANSS Total 0.83Large PSS Total 0.58 Medium NNT 95% CI PANSS Positive ≥ 20% 6 ARRextends from −ve to +ve PANSS Negative ≥ 20% 3 1.7 to 6.7 PANSS General≥ 20% 4  1.9 to 13.2 PANSS Total ≥ 20% 4  1.9 to 13.5 PSS ≥ 20% 4  1.9to 12.7 PANSS = Positive and Negative Syndrome Scale, PSS = PerceivedStress Scale, Effect Sizes: small > 0.2 to 0.5, medium > 0.5 to 0.8,Large > 0.8 or greater, CI = confidence intervals, ARR = absolute riskreduction.

Secondary Outcomes WSE treated subjects experienced significantreductions in PSS stress scores compared to placebo (Cohen's d=0.58)(FIG. 2 and Table 5). The time to significant separation in PANSSnegative, general and total symptom scores favoring WSE over placebobegan at Visit 4 (i.e. at four weeks of treatment) and was sustainedthroughout the remainder of the twelve week study (FIGS. 3A, 3B, 3C). Asimilar time course of improvement was noted in the PSS scores for theWSE group (FIG. 4).

Further analyses of the general symptoms of the PANSS scale wasconducted to assess if the depression score (single item on the PANSSscale) or the depression-anxiety cluster score (depression, guiltfeelings, anxiety and somatic concern items on the PANSS scale) or theexcitation cluster scores (excitement, poor impulse control,uncooperativeness and hostility items on the PANSS scale) improved infavor of Sensoril versus placebo. Such sub-analyses of the PANSS generalsymptoms scores has been evaluated for anti-psychotic drugs (e.g.Pueskens J, Van Baalen B, De Smedt C et al. International ClinicalPsychopharmacology, 2000, 15:343-349). In all three analyses,improvements from baseline to end of treatment significantly favoredSensoril over placebo, with medium effect sizes (Cohen's d=0.68 fordepression, 0.65 for the depression/anxiety cluster and 0.65 for theexcitation cluster), see FIGS. 5A-5C.

WSE treated patients were significantly more likely to achieve ≥20%improvements in PANSS negative, general and total symptom scores, butnot positive symptom scores, compared to those assigned to placebo(Table 5). The number needed to treat (NNT) to achieve one additionalsuch outcome with WSE ranged from three for negative symptoms (95% Cl:1.7 to 6.7), to four for general (95% Cl: 1.9 to 13.2) and totalsymptoms (95% Cl: 1.9 to 13.5) (Table 5). Twenty percent or greaterimprovement in PSS stress scores also favored the WSE group compared toplacebo (Table 5), and the NNT to achieve one additional such outcomewas four (95% Cl: 1.9 to 12.7) (Table 5). The proportion of patientsrated as improved on the CGI-Improvement subscale by the end oftreatment did not differ significantly between treatments (WSE: 12/33(36.4%) vs. Placebo: 8/33 (24.2%)).

Use of Antipsychotic and Other Psychotropic Medications Nine (27.3%) ofthe placebo assigned subjects either had their antipsychotic drug dosageincreased (n=8) or had a second antipsychotic drug added (n=1). Bycomparison, two (6.1%) WSE treated subjects had their antipsychotic drugdosage increased (Fisher's exact p=0.044). Other psychotropic medicationchanges were few and were not significantly different betweentreatments.

Inflammation Markers hsCRP and S100B levels declined in the WSE treatedgroup and increased among those assigned to placebo (See, FIGS. 6-8B).In FIG. 6, these data were skewed, and the Mann Whitney U test showed nostatistically significant differences between treatments. Clinicalsymptom improvements (PANSS or PSS) were not significantly correlatedwith S100B or hsCRP under WSE treatment. However, as shown in FIGS. 8Aand 8B, for the two markers of inflammation, one from the brain (S100B)and the other that is a peripheral marker (hsCRP), it was shown that adecrease in hsCRP levels and a decrease in S100B levels are positivelycorrelated (FIG. 8A) and this was seen only under WSE treatment(SENSORIL®, 0.621, p<0.001, n=30) but not under placebo treatment (FIG.8B, −0.271, p<0.148, n=30).

Cytokines Over 90 percent (n=60) of the subjects had detectable IL-6levels, whereas only 12%, 13.6% and 19.7% of the subjects had detectableIFN-γ, IL-4, and IL-2 levels respectively. Therefore, IL-6 was analyzed.The distribution of the IL-6 levels was right skewed and there were nostatistically significant differences between the WSE and placebo groups(Mann-Whitney U test) (FIG. 7).

Weight, Body Mass Index (BMI) and Vital Signs are indicated in FIG. 9.At the end of the treatment period, WSE treated subjects gained a meanof 2.4 lbs. compared to 1.73 lbs. in the placebo group, and BMIincreased by 0.33 mg/kg² in the WSE treated group vs. 0.20 mg/kg2 in theplacebo group; both findings were statistically non-significant.Systolic and diastolic blood pressure readings, pulse, and temperaturedifferences in the two treatment arms were not significantly differentfrom baseline to end of the treatment period.

There were no statistically significant differences between treatmentsfor adverse events that were reported at 5% in either group. The Dataand Safety Monitoring Board classified these adverse events as mild tomoderate, and they were all reported as transient (Table 6). Somnolence(21.1%), loose stool/diarrhea (18.1%), epigastric discomfort/stomachpain (9.1%), dry mouth (6.1%), hyperactivity (6.1%), rash (6.1%), andweight gain (6.1%) were more common in the WSE group, whereas headache(12.1%), anxiety (6.1%), and confusion (6.1%) were more common in theplacebo group.

TABLE 6 Adverse Events Reported at ≥5% in Either Treatment Group WSEPlacebo n = 33 n = 33 Adverse Event N % N % Gastrointestinal Disordersloose stool/diarrhea 6 (18.1) 5 (15.5) dry mouth 2 (6.1) nausea 2 (6.1)dyspepsia (heartburn) 3 (9.1) 3 (9.1) epigastric discomfort/stomach 3(9.1) 2 (6.1) pain Psychiatric Disorders anxiety 2 (6.1) hyperactive 2(6.1) confusion 2 (6.1) worsening of psychiatric 2 (6.1) 1 (3.0)symptoms Neurological/Nervous System Disorders somnolence 7 (21.1) 3(9.1) headache 2 (6.1) 4 (12.1) General Disorders fatigue/lethargy 2(6.1) 2 (6.1) Skin Manifestations rash 2 (6.1) Metabolism and Nutritionweight gain 2 (6.1) 1 (3.0) WSE = standardized extract of Withaniasomnifera

This study supports the hypothesis that a standardized extract of W.somnifera, when added adjunctively to antipsychotic medications,provides significant benefits for negative, general and total symptomsin patients with schizophrenia experiencing an exacerbation of symptoms.Patients receiving WSE also reported a significant diminution in theirlevels of perceived stress. Improvements with WSE treatment in negative,general and total symptoms were first noted at 4 weeks and continuedthrough the 12 week study period. The relatively large treatment effectsof WSE for negative, general and total symptoms of schizophrenia isespecially encouraging given that a meta-analyses of adjunctiveinflammatory agents, celecoxib and aspirin (eight studies), determined asignificant but small treatment effect size for positive symptoms(Hedges' g=−0.189), and trend level treatment effect for total symptoms(Hedges' g=−0.236), but no benefit for negative symptoms ofschizophrenia (Nitta M. et al.: Adjunctive Use of NonsteroidalAnti-inflammatory Drugs for Schizophrenia: A Meta-analytic Investigationof Randomized Controlled Trials. Schizophr Bull 2013; 39:1230-1241).Even though improvements in positive symptom scores under WSE treatmentwas not significantly better than in the placebo group, however, therewere significantly fewer anti-psychotic medication adjustments in theWSE group.

S100B is secreted by astrocytes and oligodendrocytes and is consideredto be a marker of CNS inflammation. In the present study, even thoughdeclines in S10013 levels with WSE and elevations in S100B with placebowere not significantly different between groups, WSE has knownanti-inflammatory properties, including Cox-2 inhibition, suppression ofNF-kB activation, and attenuation of pro-oxidant and inflammatoryresponses in microglial and astrocytic cells and enhancement of Nrf2/AREreporter activity in astrocytes. In stressed animals, WSE enhancestype-1 immunity, e.g., promotes normalization of IL-2 and IFN-γ levelsand significantly improves anti-oxidant and lipid peroxidation indices.Furthermore, human studies have shown that WSE induces the proliferationof CD4+ and CD8+ T cells. WSE is also known to attenuate glutamateexcitotoxicity; protect against deleterious propoxur inducedanti-cholinergic brain and cognitive dysfunction; and recover dopaminelevels and attenuate GFAP, a pro-inflammatory marker of astrocyteactivation, in a mouse model of Parkinsonism. These separate lines ofenquiry appear to point to WSE's favorable induction of type-1 cytokinesand anti-inflammatory and anti-oxidant actions (Cox-2 inhibition, impactelevated S100B levels, others) in the CNS.

The data above support the potential of WSE to reverse the type-2/type-1immunological dysfunction reported in schizophrenia.

In conclusion, WSE added adjunctively to antipsychotic medications inpatients with schizophrenia experiencing an exacerbation of symptomsprovides benefits for negative, general and total symptoms.

Example 2—Sensory and Cognitive Effects of WSE Administration toPatients with Schizophrenia

As shown below, standardized extract of W. somnifera, when added tostandard doses of marketed antipsychotic medications, improves eventrelated brain potentials, specifically: mismatch negativity, P300, andgammaband, in addition to negative symptoms in persons withschizophrenia or schizoaffective disorder.

In the present example (n=11 subjects taken from the group of 66patients of Example 1), some of the MMN deficit was recovered in personswith schizophrenia that were treated with WSE added to a standardanti-psychotic agent, compared to those subjects who received placebo,and the size of the WSE treatment effect for recovery of MMN was large(d=1.28). Furthermore this WSE treated group improved their negativesymptoms scores significantly compared to those receiving placebo.Additionally, the WSE-treated group also improved on two other corticalneurophysiological deficits compared to the placebo group: the P300 ERPand the Gamma-band steady-state response. The size of the treatmenteffect of WSE was medium for Gamma band (d=0.59) compared to placebo(d=0.07). For P300, at the end of the treatment (12 weeks), theamplitude was larger for the attend condition in the WSE treated group(d=0.47) compared to placebo (d=0.24) and also for the ignore condition(WSE, d=0.69, placebo, d=0.29).

In further detail, eleven patients with Schizophrenia or SchizoaffectiveDisorder participated in a study to evaluate the effects of astandardized extract of W. somnifera (WSE) on Mismatch Negativity. Thesepatients had experienced a recent exacerbation of symptoms and had beenreceiving standard antipsychotic agents for 4 weeks or longer. Thestandardized extract of W. somnifera (SENSORIL®) was added toanti-psychotic agents at a dosage of 250 mg twice a day for the firstweek (500 mg/day) and then increased to 500 mg twice a day (i.e. 1000mg/day) for an additional 11 weeks. Mismatch negativity was measuredbefore the patients received WSE and again at the end of the 12-weekstudy. The study was designed as a randomized, double-blind, parallelarm, placebo-controlled clinical trial. Patients and research staffconducting the neurophysiology measurements (MMN) and the psychiatricrating scales (to measure improvements in psychopathology such aspositive, negative, general or total symptoms using the Positive andNegative Syndrome Scale) were “blind” to whether patients were allocatedto WSE or placebo. Similarly, the analyses of MMN and the clinicalvariables (i.e. PANSS positive, negative, general and total symptoms)were undertaken “blind” to treatment allocation.

Event related potential (ERPs) were measured, including MMN, P300, andGamma-band. Participants watched a silent movie, and ignored repeatedtones (50 ms, 1.2 kHz, 10%) interspersed with pitch (100 ms, 1 kHz, 10%)in a MMN task, and completed two auditory oddball tasks, either countingrare pitch duration deviants (50 ms, 1.2 kHz, 15%) or ignoring allsounds. These ERPs were measured before participants received drug orplacebo and at the end of the double-blind study.

TABLE 7 demographic and illness characteristics of the 11 patients. Fivepatients were randomly assigned to WSE and six patients to placebo. WSEPlacebo (n = 5) (n = 6) Diagnosis, Schizophrenia/Schizoaffective, n 3/22/4 Age, mean (SD), y 45 47.33 (11.07) (11.52) Gender, male/female, n1/4 3/3 Age at onset of 1^(st) episode, mean (SD), y 22.8 24 (14.9)(11.09) Duration of illness, mean (SD), y 22.2 23.3 (14.38) (11.98)Number of lifetime psychiatric hospitalizations, 7.2 7.8 mean (SD) (2.8)(6.8) Atypical Antipsychotics, n 5 5 OLZ Equivalent mean (SD), mg/day16.8 15.52 (12.85) (9.39) Typical Antipsychotics, n 0 1 WSE—Standardizedextract of Withania somnifera (SENSORIL ®), SD—standard deviation,n—number, y—years, OLZ Equivalent—all anti-psychotic drugs converted toolanzapine in mg/day using the antipsychotic conversion website foundhere: Leucht S, Samara M, Heres S, et al. Dose Equivalents forAntipsychotic Drugs: The DDD Method. Schizophr Bull. 2016; (42): S90-S94

As can be seen from FIG. 10A, treatment with WSE appeared to recoversome of the mismatch negativity (MMN) deficit observed at T1 (beforetreatment), reflected in trend-level (p<0.09) improvements (largetreatment effect) in duration-deviant MMN with WSE (d=1.28) but not withplacebo at T2 (end of 12 weeks of treatment) (d=−0.27, see FIG. 10A T2in red, black arrow). An effect size—“d”>1 is typically considered a“large treatment effect” (Cohen J. Quantitative Methods in Psychology, APower Primer. Psychological Bulletin, 1992, Vol. 112. No. 1, 155-159).Importantly, in this group of 11 patients, negative symptom scoresimproved significantly under WSE treatment vs. placebo (mean±standarddeviation (SD) change scores: 4±2.24 for WSE vs. 0.33±1.97 for placebo,Mann-Whitney U 3.0, p<0.03). Expressed as percentage change in negativesymptom scores from before to end of treatment, the 5 patients treatedwith WSE improved by 22.49% (±11.58) vs. 3.20% (±12.62) (Table 8) forplacebo (Mann-Whitney U=4, p<0.046), statistical significance wasdetermined by a two-tailed test.

TABLE 8 Percentage Change in PANSS Scores WSE Placebo PANSS PANSS PANSSPANSS PANSS PANSS PANSS NSS Positive Negative General Total ID PositiveNegative General Total

5.93% 5.26%  0% 10.39% 48 11.11% −4.55% −11.76%   −9.64%

0.00% 25.93%  21.62%   25.00% 49 25.00% 11.11% 18.92% 19.35%

8.57% 16.67%  30% 26.39% 51

8.10% 12.50% 22.22% 25.00%

1.58%

1.25%  0% 18.03% 58 21.05% −13.33%   23.33% 14.06%

2.22%

3.33%  0% 12.90% 59

3.33% 18.75% 13.79% 20.63% 63  6.67% −5.26%    0%    0% Negative symbol(−) indicates worsening of symptoms

indicates data missing or illegible when filed

Improvements favoring the WSE treated group (vs. placebo) were alsonoted for P300 and Gamma band steady state potentials, FIG. 10B. In theoddball task, the WSE treated group showed a larger P300 from beforetreatment (T1) to end of treatment −T2 (attend task: d=0.47; ignore:d=0.69) compared to placebo (attend task, d=0.24, ignore, d=0.29).Gamma-band steady state potentials in the WSE group displayed greaterattention-related amplitude increase at T2 (d=0.59) than in the placebogroup (d=0.07). FIG. 10C.

The following clauses provide various, non-limiting aspects of theinvention.

1. A method of treating a psychiatric disorder for which anantipsychotic drug is administered in a patient, comprisingadministering to the patient a Withania somnifera active agent incombination with an antipsychotic active agent in amounts effective totreat the psychiatric disorder.2. The method of clause 1, wherein the psychiatric disorder is apsychotic disorder, such as schizophrenia or a schizoaffective disorder.3. The method of clause 1, wherein the psychiatric disorder is selectedfrom the group consisting of: schizophrenia; Schizophrenia, ParanoidType; Schizophrenia, Disorganized Type; Schizophrenia, UndifferentiatedType; Schizophrenia, Residual Type; Schizoaffective Disorder;Schizophreniform Disorder; Delusional Disorder; Brief PsychoticDisorder; Other specified Schizophrenia Spectrum and other PsychoticDisorder; Unspecified Schizophrenia Spectrum, and other PsychoticDisorder.4. The method of clause 2 or 3, wherein a negative symptom of thepsychiatric disorder is improved in the patient after administration ofthe W. somnifera active agent to the patient.5. The method of clause 2 or 3, wherein stress symptoms, depression,anxiety, and/or excitation symptoms of the psychiatric disorder isimproved in the patient after administration of the W. somnifera activeagent to the patient.6. The method of clause 2 or 3, wherein a sensory or cognitive symptomof the psychiatric disorder is improved in the patient afteradministration of the W. somnifera active agent to the patient.7. The method of clause 6, wherein the sensory or cognitive symptom isan electroencephalogram response to an auditory stimulus.8. The method of clause 6, wherein the electroencephalogram response isone or more of a mismatch negativity abnormality, a P300 event-relatedpotential, or a gammaband auditory steady state response.9. The method of clause 1, wherein the W. somnifera active agent isprovided in leaves and/or roots of a Withania somnifera plant or anextract of plant material, for example roots and/or leaves of a W.somnifera plant.10. The method any of one of clauses 1-9, wherein leaves and/or roots ofa Withania somnifera plant or an extract of, the roots and/or leaves of,a W. somnifera plant, or a W. somnifera active agent, are administeredin an amount effective to treat one or more negative symptoms of thepsychiatric disorder.11. The method of clause 1, wherein the W. somnifera active agent isadministered to the patient orally.12. The method of clause 1 or 2, wherein the W. somnifera active agentis administered to the patient for at least four weeks, and optionallyindefinitely.13. The method of any one of clauses 1-12, wherein the W. somniferaactive agent is provided in a standardized extract comprising:

-   -   a. at least 3% (% wt.) of withanolide glycosides and        sitoindosides;    -   b. at least 3% of oligosaccharides; and    -   c. less than 0.5% of free withaferin A (aglycone),

wherein (a):(c) is 75-95:25-5 and (a):(b) is 40-60:60-40.

14. The method of clause 13, wherein the standardized extract comprises:

-   -   a. at least 8% of withanolide glycosides and sitoindosides; and    -   b. at least 32%, of oligosaccharides.        15. The method of clause 13 or 14, wherein the oligosaccharide        has a weight average molecular weight (Mw) of less than 2000 Da.        16. The method of clause 13, wherein the standardized extract        comprises at least 8% wt. total withanolide glycoside        conjugates, 2% wt. or less withaferin A, and a ratio of        withanolide glycoside conjugates to free withaferin A ranging        from 75:95 to 25:5, optionally with % wt. determined by high        performance liquid chromatography (HPLC).        17. The method of any one of clauses 1-16, wherein the W.        somnifera active agent is administered to the patient for at        least four weeks in an amount of from 100 mg to 2000 mg twice        daily.        18. The method of clause 16, wherein the W. somnifera active        agent is administered to the patient in an amount of 250 mg        twice daily for the first week, and up to 500 mg twice daily        thereafter.        19. The method of any one of clauses 1-18, wherein the W.        somnifera active agent is a withanolide glycoside or        sitoindoside, or an aglycone derivative thereof.        20. The method of clause 19, wherein the W. somnifera active        agent includes one or more of withanolide D, sitoindoside VII,        sitoindoside VIII, sitoindoside IX, and sitoindoside X.        21. The method of any one of clauses 1-18, wherein the W.        somnifera active agent comprises:

where R¹ is H, C₁-C₃ alkyl, or C₁-C₄ alkoxyl, R² is H or C₁-C₃ alkyl, R³is H or HO, and

is a single or double bond.22. A pharmaceutical dosage form, or a composition, for use in treatmentof a psychiatric disorder for which an antipsychotic drug isadministered, comprising an antipsychotic agent and a Withania somniferaactive agent in amounts effective to treat the psychiatric disorder,such as a psychotic disorder, such as schizophrenia or schizoaffectivedisorder, and optionally one or more negative symptoms of thepsychiatric disorder.23. The pharmaceutical dosage form of clause 22, wherein the W.somnifera active agent is provided as leaves and/or roots of a W.somnifera plant or as an extract of roots and/or leaves of a W.somnifera plant.24. The pharmaceutical dosage form of clause 22, prepared as an oral orparenteral dosage form.25. The pharmaceutical dosage form of clause 22, comprising from 100 mgto 2000 mg per dose, e.g., 250 mg, 500 mg, or 1000 mg per dose, of anextract of roots and/or leaves of a W. somnifera plant.26. The pharmaceutical dosage form of clause 25, wherein the W.somnifera active agent is provided in a standardized extract comprising:

-   -   a. at least 3% (% wt.) of withanolide glycosides and        sitoindosides;    -   b. at least 3% 3-8%, of oligosaccharides; and    -   c. less than 0.5% of free withaferin A (aglycone),

wherein (a):(c) is 75-95:25-5 and (a):(b) is 40-60:60-40.

27. The pharmaceutical dosage form of clause 26, wherein thestandardized extract comprises:

-   -   a. at least 8% of withanolide glycosides and sitoindosides; and    -   b. at least 32%, of oligosaccharides.        28. The pharmaceutical dosage form of clause 26 or 27, wherein        the oligosaccharide has a weight average molecular weight (Mw)        of less than 2000 Da.        29. The pharmaceutical dosage form of clause 26, wherein the        standardized extract comprises at least 8% wt. total withanolide        glycoside conjugates, 2% wt. or less withaferin A, and a ratio        of withanolide glycoside conjugates to free withaferin A ranging        from 75:95 to 25:5, optionally with % wt. determined by high        performance liquid chromatography (H PLC).        30. The pharmaceutical dosage form of clause 22, wherein the W.        somnifera active agent comprises a withanolide glycoside or        sitoindoside, or an aglycone derivative thereof.        31. The pharmaceutical dosage form of clause 30, wherein the W.        somnifera active agent comprises: withanolide D, sitoindoside        VII, sitoindoside VIII, sitoindoside IX, sitoindoside X,        derivatives thereof, or any combination thereof.        32. The pharmaceutical dosage form of clause 22, wherein the W.        somnifera active agent comprises:

where R¹ is H, C₁-C₃ alkyl, or C₁-C₄ alkoxyl, R² is H or C₁-C₃ alkyl, R³is H or HO, and

is a single or double bond.33. A Withania somnifera active agent for use in the treatment of anegative symptom of a psychiatric disorder.34. The W. somnifera active agent of clause 33, wherein the W. somniferaactive agent is provided as leaves and/or roots of a W. somnifera plantor as an extract of roots and/or leaves of a W. somnifera plant.35. The W. somnifera active agent of clause 33, prepared as an oral orparenteral dosage form.36. The W. somnifera active agent of clause 33, comprising from 100 mgto 2000 mg per dose, e.g., 250 mg, 500 mg, or 1000 mg per dose, of anextract of roots and/or leaves of a W. somnifera plant.37. The W. somnifera active agent of clause 33, wherein the W. somniferaactive agent is provided in a standardized extract comprising:

-   -   a. at least 3% (% wt.) of withanolide glycosides and        sitoindosides;    -   b. at least 3% of oligosaccharides; and    -   c. less than 0.5% of free withaferin A (aglycone),        wherein (a):(c) is 75-95:25-5 and (a):(b) is 40-60:60-40.        38. The W. somnifera active agent of clause 37, wherein the        standardized extract comprises:    -   a. at least 8% of withanolide glycosides and sitoindosides; and    -   b. at least 32%, of oligosaccharides.        39. The W. somnifera active agent of clause 37 or 38, wherein        the oligosaccharide has a weight average molecular weight (Mw)        of less than 2000 Da.        40. The W. somnifera active agent of clause 37, wherein the        standardized extract comprises at least 8% wt. total withanolide        glycoside conjugates, 2% wt. or less withaferin A, and a ratio        of withanolide glycoside conjugates to free withaferin A ranging        from 75:95 to 25:5, optionally with % wt. determined by high        performance liquid chromatography (HPLC).        41. The W. somnifera active agent of clause 33, wherein the W.        somnifera active agent is a withanolide glycoside or        sitoindoside, or an aglycone derivative thereof.        42. The W. somnifera active agent of clause 41, wherein the W.        somnifera active agent comprises withanolide D, sitoindoside        VII, sitoindoside VIII, sitoindoside IX, sitoindoside X,        derivatives thereof, or any combination thereof.        43. The W. somnifera active agent of clause 32, comprising:

where R¹ is H, C₁-C₃ alkyl, or C₁-C₄ alkoxyl, R² is H or C₁-C₃ alkyl, R³is H or HO, and

is a single or double bond.44. The W. somnifera active agent of clause 32, wherein the psychiatricdisorder is a psychotic disorder, such as schizophrenia or aschizoaffective disorder.45. The W. somnifera active agent of clause 32, wherein the psychiatricdisorder is selected from the group consisting of: schizophrenia;Schizophrenia, Paranoid Type; Schizophrenia, Disorganized Type;Schizophrenia, Undifferentiated Type; Schizophrenia, Residual Type;Schizoaffective Disorder; Schizophreniform Disorder; DelusionalDisorder; Brief Psychotic Disorder; Other specified SchizophreniaSpectrum and other Psychotic Disorder; Unspecified SchizophreniaSpectrum, and other Psychotic Disorder.

The present invention has been described in accordance with severalexamples, which are intended to be illustrative in all aspects ratherthan restrictive. Thus, the present invention is capable of manyvariations in detailed implementation, which may be derived from thedescription contained herein by a person of ordinary skill in the art.

1-22. (canceled)
 23. A method of treating one or more negative symptomsof schizophrenia or schizoaffective disorder in a patient experiencingan exacerbation of negative symptoms, comprising: administering, to apatient experiencing an exacerbation of negative symptoms, a Withaniasomnifera active agent in combination with an antipsychotic activeagent, wherein the W. somnifera active agent is administered for atleast four weeks in an amount of from 100 mg to 2000 mg twice daily, andwherein the combination of the W. somnifera active agent and theantipsychotic active agent treats the one or more negative symptoms ofschizophrenia or schizoaffective disorder in the patient experiencing anexacerbation of negative symptoms.
 24. The method of claim 23, whereinthe W. somnifera active agent is provided in leaves or roots of a W.somnifera plant or an extract of plant material.
 25. The method of claim23, wherein the W. somnifera active agent is administered to the patientorally.
 26. The method of claim 23, wherein the W. somnifera activeagent is provided in a standardized extract comprising: a. at least 3%(% wt.) of withanolide glycosides and sitoindosides; b. at least 3% (%wt.) of oligosaccharides; and c. less than 0.5% (% wt.) of freewithaferin A (aglycone), wherein (a):(c) is 75-95:25-5 and (a):(b) is40-60:60-40.
 27. The method of claim 26, wherein the standardizedextract comprises at least 8% wt. total withanolide glycosideconjugates, 2% wt. or less withaferin A, and a ratio of withanolideglycoside conjugates to free withaferin A ranging from 75:95 to 25:5,optionally with % wt. determined by high performance liquidchromatography (HPLC).
 28. The method of claim 26, wherein theoligosaccharide has an average molecular weight (Mw) of less than 2000Da.
 29. The method of claim 23, wherein the W. somnifera active agent isa withanolide glycoside or sitoindoside, or an aglycone derivativethereof.
 30. The method of claim 23, wherein the W. somnifera activeagent includes one or more of withanolide D, sitoindoside VII,sitoindoside VIII, sitoindoside IX, sitoindoside X, and a compoundhaving the structure:

where R1 is H, C1-C3 alkyl, or C1-C4 alkoxyl, R2 is H or C1-C3 alkyl, R3is H or HO, and is a single or double bond.
 31. The method of claim 23,wherein the W. somnifera active agent is administered for at least 12weeks.
 32. The method of claim 23, wherein the W. somnifera active agentis administered for one week in an amount of 250 mg twice daily, and isthereafter administered in an amount of 500 mg twice daily for at leasteleven weeks.
 33. The method of claim 23, wherein the patient hasexperienced an exacerbation of negative symptoms for at least two weeksprior to being administered the W. somnifera active agent.
 34. Themethod of claim 23, wherein the exacerbation of negative symptomscomprises a score of at least 16 on the Positive and Negative SyndromeScale Negative Symptom Subscale (PANSS-NSS).
 35. A method of treatingone or more negative symptoms of schizophrenia or schizoaffectivedisorder in a patient experiencing an exacerbation of negative symptoms,comprising: administering to the patient experiencing an exacerbation ofnegative symptoms: a first active agent consisting of a Withaniasomnifera active agent; and a second active agent comprising anantipsychotic active agent, wherein the W. somnifera active agent isadministered for at least four weeks in an amount of from 100 mg to 2000mg twice daily, and wherein the combination of the W. somnifera activeagent and the antipsychotic active agent treats the one or more negativesymptoms of schizophrenia or schizoaffective disorder in the patientexperiencing an exacerbation of negative symptoms.
 36. The method ofclaim 35, wherein the W. somnifera active agent is administered for atleast 12 weeks.
 37. The method of claim 35, wherein the W. somniferaactive agent is administered for one week in an amount of 250 mg twicedaily, and is thereafter administered in an amount of 500 mg twice dailyfor at least eleven weeks.
 38. The method of claim 35, wherein thepatient has experienced an exacerbation of negative symptoms for atleast two weeks prior to being administered the W. somnifera activeagent.
 39. The method of claim 35, wherein the exacerbation of negativesymptoms comprises a score of at least 16 on the Positive and NegativeSyndrome Scale Negative Symptom Subscale (PANSS-NSS).
 40. A method oftreating one or more negative symptoms of schizophrenia orschizoaffective disorder in a patient, comprising: administering, to apatient a Withania somnifera active agent in combination with anantipsychotic active agent, wherein the patient exhibits a score of atleast 4 for at least two symptoms of the Positive and Negative SyndromeScale Negative Symptom Subscale (PANSS-NSS), wherein the W. somniferaactive agent is administered for one week in an amount of 250 mg twicedaily, and is thereafter administered in an amount of 500 mg twice dailyfor at least eleven weeks, wherein the combination of the W. somniferaactive agent and the antipsychotic active agent treats the one or morenegative symptoms of schizophrenia or schizoaffective disorder in thepatient.
 41. The method of claim 40, wherein the W. somnifera activeagent includes one or more of withanolide D, sitoindoside VII,sitoindoside VIII, sitoindoside IX, sitoindoside X, and a compoundhaving the structure:

where R1 is H, C1-C3 alkyl, or C1-C4 alkoxyl, R2 is H or C1-C3 alkyl, R3is H or HO, and is a single or double bond.
 42. The method of claim 40,wherein the W. somnifera active agent is provided in a standardizedextract comprising: a. at least 8% (% wt.) of withanolide glycosides andsitoindosides; b. at least 32% (% wt.) of oligosaccharides; and c. lessthan 0.5% (% wt.) of free withaferin A (aglycone), wherein (a):(c) is75-95:25-5 and (a):(b) is 40-60:60-40.